Skin cream ingredient may stop Parkinson's effects on brain

The active ingredient in an over-the-counter skin cream may slow or stop the effects of Parkinson's disease on brain cells, scientists have found.
Scientists are now testing the drug, called kinetin, in animal models of Parkinson's.
"Kinetin is a great molecule to pursue because it's already sold in drugstores as a topical anti-wrinkle cream," said Howard Hughes Medical Institute (HHMI) investigator Kevan Shokat of the University of California, San Francisco.
"So it's a drug we know has been in people and is safe," Shokat said.
Parkinson's disease is a degenerative disease that causes the death of neurons in the brain. Initially, the disease affects one's movement and causes tremors, difficulty walking, and slurred speech. Later stages of the disease can cause dementia and broader health problems.

In 2004, researchers studying an Italian family with a high prevalence of early-onset Parkinson's disease discovered mutations in a protein called PINK1 associated with the inherited form of the disease.

Since then, studies have shown that PINK1 normally wedges into the membrane of damaged mitochondria inside cells that causes another protein, Parkin, to be recruited to the mitochondria, which are organelles responsible for energy generation.
Neurons require high levels of energy production, therefore when mitochondrial damage occurs, it can lead to neuronal death.
However, when Parkin is present on damaged mitochondria, studding the mitochondrial surface, the cell is able to survive the damage.

In people who inherit mutations in PINK1, however, Parkin is never recruited to the organelles, leading to more frequent neuronal death than usual.
Shokat and his colleagues wanted to develop a way to turn on or crank up PINK1 activity, therefore preventing an excess of cell death, in those with inherited Parkinson's disease.
Researchers began investigating how PINK1 binds to ATP, the energy molecule that normally turns it on. In one test, instead of adding ATP to the enzymes, they added different ATP analogues, versions of ATP with altered chemical groups that slightly change its shape.
Scientists typically must engineer new versions of proteins to be able to accept these analogs, since they don't fit into the typical ATP binding site.

However, one of the analogs - kinetin triphosphate, or KTP - turned on the activity of not only normal PINK1, but also the mutated version, which doesn't bind ATP.
Adding the precursor of KTP, kinetin, to cells - both those with PINK1 mutations and those with normal physiology - amplified the activity of PINK1, increased the level of Parkin on damaged mitochondria, and decreased levels of neuron death, researchers found.